The initial results of the trial, dubbed CLEOPATRA, were presented on December 7, 2011, at the San Antonio Breast Cancer Symposium (SABCS) and published the same day in the New England Journal of Medicine. Those results showed that combining both HER2-targeting agents with the chemotherapy drug docetaxel as initial treatment led to a 6-month improvement in progression-free survival compared with treatment with trastuzumab and docetaxel.

Although both drugs target the HER2 protein on the surface of cancer cells, they do so in different ways. Laboratory studies have indicated that the drugs may have a synergistic effect on HER2-positive tumors, which, the trial investigators explained, are “addicted” to HER2 signaling.

More than 800 women were enrolled in the randomized trial; half received all three drugs, and half received trastuzumab and docetaxel, a standard first-line treatment for women with metastatic HER2-positive breast cancer, plus a placebo. Median progression-free survival was 18.5 months in the three-drug arm and 12.4 months in the two-drug-plus-placebo arm. More women who received the three-drug combination experienced substantial shrinkage of their tumors than women who received the standard treatment.

Trastuzumab has been associated with significant cardiac side effects in some women, but no increase in such side effects was seen in women in the trial who received both HER2-targeted drugs.

The initial analysis showed a trend toward better overall survival in women treated with both HER2-targeting agents than in women treated with trastuzumab, but the study had not gone on long enough for the survival data to be definitive.

The study investigators presented the final results of the trial at the European Society for Medical Oncology 2014 Congress in Madrid. After a median follow-up of 50 months, the women treated with both HER2-targeted agents lived 15.7 months longer than those treated with trastuzumab, with a median overall survival of 56.5 months versus 40.8 months, respectively. The final results were also published in NEJM on February 19, 2015.

“The survival improvement of nearly 16 months … is unprecedented among studies of metastatic breast cancer,” said the study’s lead author, Sandra Swain, M.D., of Medstar Washington Hospital Center in Washington, DC. Patients in the trastuzumab-docetaxal group whose disease progressed were allowed to cross over to the pertuzumab-trastuzumab-docetaxel group, but the overall survival analysis was not adjusted for this crossover, Dr. Swain explained. “As such, this is a very conservative final analysis of survival.”

The Food and Drug Administration approved pertuzumab on June 8, 2012, for use in combination with trastuzumab and docetaxel to treat women with HER2-positive metastatic breast cancer. This approval was based on the earlier progression-free survival results.

Updated: February
26, 2015

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